Brain-type natriuretic peptide (BNP, also called nesiritide) is one of a family of peptides that are involved in cardiovascular, renal, and endocrine homeostasis. It was discovered in 1988, almost a decade after the discovery of atrial natriuretic peptide (ANP). Although it was first isolated from porcine brain, it is known for its activity at receptors in vascular smooth muscle and endothelial cells. BNP is an endogenous peptide produced by the heart. It is first produced as prepro-BNP and is subsequently shortened twice to the active form, a 32-amino acid peptide with one disulfide bond.
BNP binds to the natriuretic peptide receptor A (NPR-A), a membrane bound protein on the cell surface. The binding event triggers the synthesis of cGMP in the cytosol by guanylate cyclase. It is through this secondary messenger that BNP accomplishes the cardio-vascular, renal, and endocrine effects with which it is associated. Regulation of BNP is accomplished by several different means. BNP molecules that bind to NPR-A and stimulate cGMP production are removed from circulation, but there are other means by which BNP is eliminated without invoking a response. The most common means of removal is through binding to the clearance receptor, natriuretic peptide receptor C (NPR-C). Upon binding to NPR-C, the peptide is taken into the cell and cleaved enzymatically. The next major means of clearance is degradation by neutral endopeptidase (NEP), which is a membrane-bound enzyme on the cell surface. Finally, BNP is removed to a small extent by renal filtration.
Under normal conditions, BNP is produced in low amounts in the atria and ventricles. However, when the ventricles are stretched during cardiac decompensation, the amount of BNP that is produced increases greatly. Although the atria are still involved, the ventricles become the main site of production. The heart produces BNP in response to a stretching of the ventricles that occurs during decompensation at the outset of congestive heart failure (CHF). The effects of BNP include natriuresis, diuresis, vasodilation, and a lowering of diastolic blood pressure. These effects are brought about through the actions of a secondary messenger, cyclic guanosine monophosphate (cGMP). Production of cGMP is triggered when BNP interacts with the natriuretic peptide receptor A (NPR-A) which is a membrane-bound receptor located on the surface of endothelial cells in blood vessels, kidneys, and lungs. Plasma concentration of BNP incrementally increases with increased severity of CHF. Despite this increase, the beneficial effects of BNP are blunted in severe CHF, raising the possibility of a relative deficiency state in overt CHF. Alternatively, as the assays currently employed to measure plasma concentration of BNP do not specifically differentiate between pre-pro BNP and the mature form, this pro-hormone may not be adequately processed to its mature form in overt CHF. Therefore, either the amount of BNP that the heart can produce is overcome or prepro-BNP is not adequately converted into its active form, thus reducing its beneficial actions. Because of its early production at the onset of heart disease, BNP has become important as a diagnostic marker to detect patients who are at high risk of developing CHF.
BNP functions to relieve cardiac decompensation in several ways. BNP leads to the excretion of sodium and an increase in urine output, which lessen congestion. It also functions as a vasodilator, the effects of which are enhanced by several other actions. Most notable of these functions are the roles BNP plays in the interference of the renin-angiotensin-aldosterone system (RAAS). It leads to inhibition of renin, which is a key enzyme in the generation of the vasoconstrictive peptide angiotensin. It inhibits the overgrowth of epithelial cells lining vascular tissue, which left unchecked, can greatly reduce blood flow. A final way that BNP functions to relieve cardiac decompensation is its lusitropic effects. It improves myocardial relaxation of the ventricles, resulting in lower diastolic blood pressure.
In 2001, human BNP was approved by the FDA under the trade name NATRECOR (Nesiritide), for the treatment of acute congestive heart failure. NATRECOR. was the first drug approved for the treatment of CHF in over twelve years. It is administered by intravenous continuous infusion over a period of 48 hours. As the drug is expensive and requires hospitalization, NATRECOR is only used for the most acute cases.
Normally, peptides suffer from a short in vivo half life, sometimes mere minutes, making them generally impractical, in their native form, for administration. Thus there exists a need in the art for modified nesiritide peptides having an enhanced half-life and/or reduced clearance as well as additional advantages as compared to the nesiritide peptides in their unmodified form.